Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDUULBQ)

• DOT Name: E3 ubiquitin-protein ligase RFWD3 (RFWD3)
• Synonyms: EC 2.3.2.27; RING finger and WD repeat domain-containing protein 3; RING finger protein 201
• Gene Name: RFWD3
• Related Disease:
  Fanconi anemia complementation group A
  Neoplasm of testis
  Non-small-cell lung cancer
  Plasma cell myeloma
  Testicular germ cell tumor
  Fanconi's anemia
  Fanconi anemia, complementation group W
  Tourette syndrome
• UniProt ID: RFWD3_HUMAN
• PDB ID: 6CVZ
• EC Number: 2.3.2.27
• Pfam ID: PF13639
• Sequence:
  MAHEAMEYDVQVQLNHAEQQPAPAGMASSQGGPALLQPVPADVVSSQGVPSILQPAPAEV
  ISSQATPPLLQPAPQLSVDLTEVEVLGEDTVENINPRTSEQHRQGSDGNHTIPASSLHSM
  TNFISGLQRLHGMLEFLRPSSSNHSVGPMRTRRRVSASRRARAGGSQRTDSARLRAPLDA
  YFQVSRTQPDLPATTYDSETRNPVSEELQVSSSSDSDSDSSAEYGGVVDQAEESGAVILE
  EQLAGVSAEQEVTCIDGGKTLPKQPSPQKSEPLLPSASMDEEEGDTCTICLEQWTNAGDH
  RLSALRCGHLFGYRCISTWLKGQVRKCPQCNKKARHSDIVVLYARTLRALDTSEQERMKS
  SLLKEQMLRKQAELESAQCRLQLQVLTDKCTRLQRRVQDLQKLTSHQSQNLQQPRGSQAW
  VLSCSPSSQGQHKHKYHFQKTFTVSQAGNCRIMAYCDALSCLVISQPSPQASFLPGFGVK
  MLSTANMKSSQYIPMHGKQIRGLAFSSYLRGLLLSASLDNTIKLTSLETNTVVQTYNAGR
  PVWSCCWCLDEANYIYAGLANGSILVYDVRNTSSHVQELVAQKARCPLVSLSYMPRAASA
  AFPYGGVLAGTLEDASFWEQKMDFSHWPHVLPLEPGGCIDFQTENSSRHCLVTYRPDKNH
  TTIRSVLMEMSYRLDDTGNPICSCQPVHTFFGGPTCKLLTKNAIFQSPENDGNILVCTGD
  EAANSALLWDAASGSLLQDLQTDQPVLDICPFEVNRNSYLATLTEKMVHIYKWE
• Function: E3 ubiquitin-protein ligase required for the repair of DNA interstrand cross-links (ICL) in response to DNA damage. Plays a key role in RPA-mediated DNA damage signaling and repair. Acts by mediating ubiquitination of the RPA complex (RPA1, RPA2 and RPA3 subunits) and RAD51 at stalled replication forks, leading to remove them from DNA damage sites and promote homologous recombination. Also mediates the ubiquitination of p53/TP53 in the late response to DNA damage, and acts as a positive regulator of p53/TP53 stability, thereby regulating the G1/S DNA damage checkpoint. May act by catalyzing the formation of short polyubiquitin chains on p53/TP53 that are not targeted to the proteasome. In response to ionizing radiation, interacts with MDM2 and enhances p53/TP53 ubiquitination, possibly by restricting MDM2 from extending polyubiquitin chains on ubiquitinated p53/TP53. Required to translesion DNA synthesis across DNA-protein cross-link adducts by catalyzing ubiquitination of proteins on single-stranded DNA (ssDNA).

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fanconi anemia complementation group A	DIS8PZLI	Strong	Genetic Variation	[1]
Neoplasm of testis	DISK4XHT	Strong	Genetic Variation	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[3]
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[4]
Testicular germ cell tumor	DIS5RN24	Strong	Genetic Variation	[5]
Fanconi's anemia	DISGW6Q8	Supportive	Autosomal recessive	[6]
Fanconi anemia, complementation group W	DISK0Y1G	Limited	Unknown	[6]
Tourette syndrome	DISX9D54	No Known	Unknown	[7]

13 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of E3 ubiquitin-protein ligase RFWD3 (RFWD3).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of E3 ubiquitin-protein ligase RFWD3 (RFWD3).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of E3 ubiquitin-protein ligase RFWD3 (RFWD3).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase RFWD3 (RFWD3).	[11]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of E3 ubiquitin-protein ligase RFWD3 (RFWD3).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of E3 ubiquitin-protein ligase RFWD3 (RFWD3).	[13]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of E3 ubiquitin-protein ligase RFWD3 (RFWD3).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of E3 ubiquitin-protein ligase RFWD3 (RFWD3).	[14]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of E3 ubiquitin-protein ligase RFWD3 (RFWD3).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of E3 ubiquitin-protein ligase RFWD3 (RFWD3).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of E3 ubiquitin-protein ligase RFWD3 (RFWD3).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of E3 ubiquitin-protein ligase RFWD3 (RFWD3).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of E3 ubiquitin-protein ligase RFWD3 (RFWD3).	[22]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of E3 ubiquitin-protein ligase RFWD3 (RFWD3).	[15]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of E3 ubiquitin-protein ligase RFWD3 (RFWD3).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of E3 ubiquitin-protein ligase RFWD3 (RFWD3).	[20]

References

• [1] RPA-Mediated Recruitment of the E3 Ligase RFWD3 Is Vital for Interstrand Crosslink Repair and Human Health.Mol Cell. 2017 Jun 1;66(5):610-621.e4. doi: 10.1016/j.molcel.2017.04.021.
• [2] Meta-analysis identifies four new loci associated with testicular germ cell tumor.Nat Genet. 2013 Jun;45(6):680-5. doi: 10.1038/ng.2634. Epub 2013 May 12.
• [3] Identification of an E3 ligase-encoding gene RFWD3 in non-small cell lung cancer.Front Med. 2020 Jun;14(3):318-326. doi: 10.1007/s11684-019-0708-6. Epub 2019 Sep 28.
• [4] Genome-wide association study identifies multiple susceptibility loci for multiple myeloma.Nat Commun. 2016 Jul 1;7:12050. doi: 10.1038/ncomms12050.
• [5] Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor.Nat Genet. 2017 Jul;49(7):1133-1140. doi: 10.1038/ng.3896. Epub 2017 Jun 12.
• [6] Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia. J Clin Invest. 2017 Aug 1;127(8):3013-3027. doi: 10.1172/JCI92069. Epub 2017 Jul 10.
• [7] De Novo Coding Variants Are Strongly Associated with Tourette Disorder. Neuron. 2017 May 3;94(3):486-499.e9. doi: 10.1016/j.neuron.2017.04.024.
• [8] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [9] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [10] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [11] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [12] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [13] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [14] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [15] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [16] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [17] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [18] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [19] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [20] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [21] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.